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. 2009 Nov;107(5):1579-90.
doi: 10.1152/japplphysiol.91629.2008. Epub 2009 Sep 3.

Prenatal nicotine-exposure alters fetal autonomic activity and medullary neurotransmitter receptors: implications for sudden infant death syndrome

Jhodie R Duncan  1 , Marianne Garland, Michael M Myers, William P Fifer, May Yang, Hannah C Kinney, Raymond I Stark
Affiliations

Prenatal nicotine-exposure alters fetal autonomic activity and medullary neurotransmitter receptors: implications for sudden infant death syndrome

Jhodie R Duncan et al. J Appl Physiol (1985). 2009 Nov.

Abstract

During pregnancy, exposure to nicotine and other compounds in cigarette smoke increases the risk of the sudden infant death syndrome (SIDS) two- to fivefold. Serotonergic (5-HT) abnormalities are found, in infants who die of SIDS, in regions of the medulla oblongata known to modulate cardiorespiratory function. Using a baboon model, we tested the hypothesis that prenatal exposure to nicotine alters 5-HT receptor and/or transporter binding in the fetal medullary 5-HT system in association with cardiorespiratory dysfunction. At 87 (mean) days gestation (dg), mothers were continuously infused with saline (n = 5) or nicotine (n = 5) at 0.5 mg/h. Fetuses were surgically instrumented at 129 dg for cardiorespiratory monitoring. Cesarean section delivery and retrieval of fetal medulla were performed at 161 (mean) dg for autoradiographic analyses of nicotinic and 5-HT receptor and transporter binding. In nicotine-exposed fetuses, high-frequency heart rate variability was increased 55%, possibly reflecting increases in the parasympathetic control of heart rate. This effect was more pronounced with greater levels of fetal breathing and age. These changes in heart rate variability were associated with increased 5-HT(1A) receptor binding in the raphé obscurus (P = 0.04) and increased nicotinic receptor binding in the raphé obscurus and vagal complex (P < 0.05) in the nicotine-exposed animals compared with controls (n = 6). The shift in autonomic balance in the fetal primate toward parasympathetic predominance with chronic exposure to nicotine may be related, in part, to abnormal 5-HT-nicotine alterations in the raphé obscurus. Thus increased risk for SIDS due to maternal smoking may be partly related to the effects of nicotine on 5-HT and/or nicotinic receptors.

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Figures

Fig. 1.
Fig. 1.
Heart rate variability. A: time domain measure of high-frequency heart period variability [root mean square of successive differences in RR intervals (RMSSD), means ± SE] at four levels of fetal breathing activity (in %time: none = 0, low = 1–33, mid = 34–67, high = >67) at 139–145 days gestation (dg). Dashed lines, nicotine-exposed fetuses (n = 5); solid lines, controls (n = 5). B: RMSSD vs. breathing at 146–152 dg. C: relationship between amount of nicotinic acetylcholine receptor (nAChR) subunit binding (3H-epibatidine) in the dorsal motor nucleus of the vagus (DMX) and RMSSD during periods of high fetal breathing activity (>67% of time) during late gestation (146–152 dg).
Fig. 2.
Fig. 2.
nAChR and serotonin (5-HT) markers in the fetal baboon medulla. Pseudocolored autoradiographic images of 3H-epibatidine binding to α2–4-, β2-, and β4-nAChRs (A and B), 125I-bungrotoxin binding to α7-nAChRs (C and D), [3H]8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tertraline] binding to 5-HT1A receptors (E and F), 125I-DOI (2,5-dimethoxy-4-iodoamphetamine) binding to 5-HT2A receptors (G and H), and 125I-RTI-55 [3β-(4-iodophenyl)tropan-2 β-carboxylic acid methyl ester] binding to the 5-HT transporter (I and J) in the fetal baboon medulla with specific activity scales for control (left) and nicotine-exposed (right) fetuses with corresponding graphs of binding levels in select nuclei for each group (fmol/mg tissue). Nicotine exposure resulted in a global increase in 3H-epibatidine binding (B) and an increase in [3H]8-OH-DPAT binding in the raphé obscurus (RO) (F). HG, hypoglossal nucleus; ION, inferior olivary nucleus; NTS; nucleus of the solitary tract; PGCL, paragigantocellularis lateralis.
Fig. 3.
Fig. 3.
Colocalization of α4-nAChRs and 5-HT neurons in the fetal baboon medulla. A, D, G, and J: PH8, a marker for tryptophan hydroxylase, the key enzyme in the synthesis of 5-HT, immunopositive neurons (green). B, E, H, and K: α4 immunopositive cells (red) in the raphé obscurus (A–F) and extra-raphé (paragigantocellularis lateralis) (G–L) at 161 days of gestation (term = 180 days). C, F, I, and L: colocalization of expression is demonstrated by merging of images (yellow). A subpopulation of neurons expressing α4, which were not 5-HT, were observed in association to 5-HT cells. Scales: A–C: 115 μm; D–F: 57 μm; G–I: 30 μm; J–L: 35 μm.
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